Re: Gilead will acquire Calistoga and CAL101 - FDA

[Guest guest]

re: Are these official, publicly published or presented rules (or

> guidelines) for CAL-101 (and other new CLL drugs)? or are they

> unofficial discussions between the FDA and the drug sponsors (e.g. Calistoga)?

Hi Al, The same principles must apply for all drugs, but the recommended

methods can vary depending on what it takes to demonstrate a drug provides

clinical benefit in different kinds of cancers and clinical settings. (Testing

in the refractory setting is typically the fastest path to approval - your drug

works when nothing else does - fills an unmet urgent medical need.)

See http://www.lymphomation.org/endpoints.pdf for principles of drug approvals

in oncology and many examples.

copying: " The FDA grants either regular marketing approval

or accelerated marketing approval for oncology

drug applications.

Regular approval is based on end points that demonstrate that the drug provides

a longer life, a better life, or a favorable effect on an established surrogate

for a longer life or a better life.

Accelerated approval (AA) is based on a surrogate end point that is less well

established but that is reasonably likely to predict a longer or a better life.

Tumor response was the approval basis in 26 of 57 regular approvals, supported

by relief of tumor-specific symptoms in nine of these 26 regular approvals.

Relief of tumor-specific symptoms provided critical support for approval in 13

of 57 regular approvals. Approval was based on tumor response in 12 of 14 AAs. "

Karl

> >Don't forget the FDA and their rules on " is it needed " , " does it

> >really make a difference " , don't we have something like this already? "

>

> Are these official, publicly published or presented rules (or

> guidelines) for CAL-101 (and other new CLL drugs)? or are they

> unofficial discussions between the FDA and the drug sponsors (e.g. Calistoga)?

>

> Al Janski

[Guest guest]

>re: Are these official, publicly published or presented rules (or

>guidelines) for CAL-101 (and other new CLL drugs)? or are they

>unofficial discussions between the FDA and the drug sponsors (e.g. Calistoga)?

At 04:40 PM 2/24/2011, karls@... wrote:

>The same principles must apply for all drugs, .........

Generally, that is true, but I was referring to something more

specific (from previous discussions of CAL-101 & PCI-32765) that was

posted by Dr. Furman on Jan.1, which sparked discussions in several

threads last month on this listserve.

The following is a portion of Dr. Furman's post. Note Dr. Furman's

concern that the " unmet medical need " would no longer be a criteria

for approval of CLL drugs.

------------

Re: Barriers to clinical trials

At 01:15 PM 1/1/2011, Rick Furman, MD wrote:

The FDA approvals are based primarily on not just benefit. The two

criteria used are:

1) greater benefit than the currently approved therapies (requires

head to head comparisons)

2) unmet medical need (nothing approved to compare with)

The FDA has suggested that it will not allow any drugs to be further

approved for CLL using the unmet medical need criteria. This is how

alemtuzumab and ofatumumab have gained approval. Thus, a trial of

drug X in patients who have disease that is refractory to

fludarabine, bendamustine, alemtuzumab, and ofatumumab will not lead

to approval. Even if this agent (like PCI-32765 or CAL-101) has a

90% rate of clinical benefit / response.

Likewise, for some very unexplicable reason, the FDA will not allow

multiple drugs to be approved at the same indication. There are 25

different anti-hypertensives and 10 different cholesterol lowering

agents. They did not have to prove themselves better than the

currently available therapies. Just that they were efficacious. Why

not the same thing for oncology drugs?

Why can we not just show CAL-101 benefits patients and get it approved?

Additionally, the FDA will not approve an agent that is equally

effective, but less toxic over the current standard of care. This

would require a large study secondary to statistical reasons, but

once done, would be a much easier means to approve these new agents.

Re: FDA criteria & new types of therapies

At 03:03 PM 1/3/2011, rrfurman wrote:

Alot of what the FDA intends is based upon statements made during the

evaluation of other agents. Much of this is not published,.....

-------- end of quote by Dr. Furman --------

Not allowing drugs to be approved for CLL using the unmet medical

need criteria, leaves only approval based on greater benefit than the

currently approved therapies in head to head comparisons.

" Equally effective, but less toxic " may be therapeutic niche into

which CAL-101 may best fit and provide the greatest benefit for

certain groups of CLL patients. For example, I believe that

untreated CLL patients who have slowly progressed to a point of

needing treatment may be particularly benefited by an agent (like

CAL-101) that provides incomplete (but manageable) disease

elimination with low levels of toxicity.

It would be unfortunate if that is not an option for an endpoint, as

Dr. Furman fears.

Dr. Furman's comment " Why not the same thing for oncology drugs? "

implied these FDA suggestions were to apply only for oncology drugs.

Dr. Furman had thought these specific suggestions were not published.

At 04:40 PM 2/24/2011, karls@... wrote:

>See http://www.lymphomation.org/endpoints.pdf for principles of

>drug approvals in oncology

This is 2003 document, and Dr. Furman's comments infer more recent

FDA suggestions.

As we discussed in posts on another thread ( " FDA criteria &

" Non-Inferiority " trials " ) last month, the more recent 2010 FDA

guidance of " non-inferiority " (link below) would be a possible

pathway for the head-to-head comparisons of CAL-101 with an approved

CLL drug. However, these 2010 guidances do not seem to be the FDA

suggestions referenced above by Dr. Furman.

At 04:22 PM 1/3/2011, " karlamonyc " wrote:

>Guidance for Industry Non-Inferiority Clinical Trials (March/2010)

>http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid\

ances/UCM202140.pdf

Al Janski

======

At 04:40 PM 2/24/2011, karls@... wrote:

>Hi Al, The same principles must apply for all drugs, but the

>recommended methods can vary depending on what it takes to

>demonstrate a drug provides clinical benefit in different kinds of

>cancers and clinical settings. (Testing in the refractory setting is

>typically the fastest path to approval - your drug works when

>nothing else does - fills an unmet urgent medical need.)

>

>See http://www.lymphomation.org/endpoints.pdf for principles of

>drug approvals in oncology and many examples.

>

>copying: " The FDA grants either regular marketing approval or

>accelerated marketing approval for oncology drug applications.

>

>Regular approval is based on end points that demonstrate that the

>drug provides a longer life, a better life, or a favorable effect on

>an established surrogate for a longer life or a better life.

>

>Accelerated approval (AA) is based on a surrogate end point that is

>less well established but that is reasonably likely to predict a

>longer or a better life.

>

>Tumor response was the approval basis in 26 of 57 regular approvals,

>supported by relief of tumor-specific symptoms in nine of these 26

>regular approvals. Relief of tumor-specific symptoms provided

>critical support for approval in 13 of 57 regular approvals.

>Approval was based on tumor response in 12 of 14 AAs. "

>

>Karl

[Guest guest]

My sense of it is that FDA tries to provide a level playing field, which can be

challenging given the heterogeneity - each cancer is unique as are the clinical

settings that will be used to select the population studied.

And it's the company that must give the okay to disclose areas of disagreement

with FDA about proposed study design and endpoints... FDA, by law, can't

disclose this information.

If the rules are different for CAL101, the patient community should be made

aware of the details so we can weigh in. We are, after all, the primary

stakeholders.

Karl

>

>

> >re: Are these official, publicly published or presented rules (or

> >guidelines) for CAL-101 (and other new CLL drugs)? or are they

> >unofficial discussions between the FDA and the drug sponsors (e.g.

Calistoga)?